1. Field of the Invention
Applicant""s invention relates to medicaments and treatment procedures relating to connective tissue disorders manifested by sub-dermal plaque accumulations as well as to fibrosis of muscle tissues, some example of which result in total or partial erectile dysfunction. Representative examples of such sub-dermal plaque accumulation disorders include Peyronie""s Disease, Ledderhose Fibrosis, Dupuytren""s contracture of the hand and certain forms of erectile dysfunction.
2. Background Information
A. Peyronie""s Disease
An initial focus of the present inventionxe2x80x94Peyronie""s diseasexe2x80x94has likely plagued men for time immemorial, but has been recognized as a distinct malady for no less than 400 years. Peyronie""s disease was first described in 1743 by a French surgeon, Francois de la Peyronie. The disease was written about as early as 1687 and was oftentimes associated with impotence.
As with the other plaque manifested disorders to which the present invention relates, the symptoms of Peyronie""s disease and of its severity vary to some degree. The most common manifestation of Peyronie""s disease is in the form of a xe2x80x9clump,xe2x80x9d xe2x80x9cplaquexe2x80x9d or xe2x80x9chardxe2x80x9d area in the non-erect penis. With or without these palpable symptoms, painful erections and penile disfigurement are often associated with the malady.
The pain and disfigurement associated with Peyronie""s disease relate to the physical structure of the penis in which is found two erectile rods, called the corpora cavernosa, a conduit (the urethra) through which urine flows from the bladder, and the tunica which separates the cavernosa from the outer layers of skin of the penis. A person exhibiting Peyronie""s disease will have formation(s) of plaque or scar tissue between the tunica and these outer layers of the skin (referred to as xe2x80x9csub-dermalxe2x80x9d in this application). The scaning or plaque accumulation of the tunica reduces its elasticity causes such that, in the affected area, it will not stretch to the same degree (if at all) as the surrounding, unaffected tissues. Thus, the erect penis bends in the direction of the scar or plaque accumulation, often with associated pain of some degree.
Peyronie""s disease often occurs in a mild form and heals spontaneously in 6 to 15 months. However, in severe cases, the hardened plaque substantially reduces penile flexibility and causes excruciating pain as the penis is forced into a highly arcuate or even serpentine configuration. A plaque on the top of the shaft (most common) causes the penis to bed upward; a plaque on the underside causes it to bend downward. In some cases, the plague develops on both top and bottom, leading to indentation and shortening of the penis.
In all but minor manifestations of Peyronie""s disease, the victim has some degree of sexual dysfunction. In more severe cases, sexual intercourse is either impossible, or is so painful as to be effectively prohibitive.
While plaque of Peyronie""s disease is itself benign, or noncancerous, this is of little solace to sufferers of the disease.
Empirical evidence indicates an incidence of Peyronie""s disease in approximately one percent of the male population. Although the disease occurs mostly in middle-aged men, younger and older men can acquire it. About 30 percent of men with Peyronie""s disease also develop fibrosis (hardened cells) in other elastic tissues of the body, such as on the hand or foot. Common example of such other conditions include Dupuytren""s contracture of the hand and Ledderhose Fibrosis of the foot.
Many researchers believe the plaque of Peyronie""s disease develops following trauma to the penis (hitting or bending) that causes localized bleeding inside the penis. If the penis is abnormally bumped or bent, an area where the septum attaches to the elastic fibers surrounding the corpora cavernosa may stretch beyond its normal limit, injuring the lining of the erectile chamber and, for example, rupturing small blood vessels. Also, as a result of aging, diminished elasticity near the point of attachment to the septum may tend to increase the chances of injury of this nature.
Such a damaged area may heal slowly or abnormally because of repeated trauma to the same area and/or because of the natural, minimal amount of blood-flow in the sheath-like fibers of the elastic structures of the penis. In cases of Peyronie""s disease which tend to heal within about a year, the plaque does not tend to advance beyond an initial inflammatory phase. In cases that persist for longer periods, the plaque typically undergoes fibrosis, or the formation of tough fibrous tissue, and even calcification, or the formation of calcium deposits.
While trauma might explain acute cases of Peyronie""s disease, it does not explain why most cases develop slowly and with no apparent traumatic event. It also does not explain why some cases disappear quickly, and why similar conditions, such as Dupuytren""s contracture, do not seem to result from severe trauma.
In some cases, men who are related by blood tend to develop Peyronie""s disease, which suggests a possible genetic predisposition to Peyronie""s disease.
B. Present Treatment of Peyronie""s Disease
Because the cause(s) and development of Peyronie""s disease are not well understood, physicians to this day treat the disease with a largely experimental approachxe2x80x94they discontinue anything which lacks apparent efficacy, and continue anything that seems to help.
Surgery is the only approach to treating Peyronie""s disease which appears to have predictably repeatable efficacy. Surgery is usually only indicated in long-term cases where the disease is stabilized and the deformity prevents intercourse and/or causes extreme pain. However, complications can develop from surgery, including a permanent shortening of the penis.
Attempts at simple plaque excision were described in the 19th century by MaClellan, Regnoli and Huitfield, but by the early 20th century most authors described this technique as disastrous. For this reason Young developed a procedure that simply xe2x80x9cfreedxe2x80x9d the plaque from the tunica albuginea in order to improve erectile dynamics. Lowsely and Boyce then re-explored the technique of simple plaque excision by adding the interposition of a xe2x80x9cpat-padxe2x80x9d graft into the defect. Although many others continued to report success with this technique, it failed to gain general acceptance as the treatment of choice.
In 1995 Nesbit described the correction of congenital penile curvature with multiple elliptical excisions of the corporeal tunica. To this day, many surgeons prefer this technique for the correction of the Peyronie""s bend. However, the inevitable penile shortening led Devine and Horton (1974) to experiment with further grafting procedures. Having experimented with fascial, arterial and venous patches in dogs, they came to the conclusion that dermal grafts were the least likely to xe2x80x9ccontractxe2x80x9d and so reproduce the defect. To this day, many other grafting materials have been tried including autologous vein, temporoparietal fascia, tunica vaginalis, gortex and dacron.
The cost of the various surgical approaches to Peyronie""s disease (no less than around $6,500) is, alone, often a deterrent to many Peyronie""s disease sufferers in adopting this particular approach to treatment. While surgical intervention was, prior to the present invention, the most likely effective treatment in any given case of Peyronie""s disease, the condition does often reappear, even after surgery.
The other, presently known, non-surgical approaches to Peyronie""s disease treatment are many and varied, although they are all largely ineffective. Attempts to dissolve the plaque by direct intra-lesional injections have been tried since the late 19th century. Walsham and Spencer injected both mercury and iodide and intra-lesional injections of fibrinolysins were used in the 1820""s. Teasley introduced the concept of intra-lesional steroid injections in 1954, although the pain caused by the high injection pressures led many surgeons to perform the procedure under general anaesthetic. In 1959 Hinman developed a xe2x80x9chigh pressurexe2x80x9d screw-threaded injection device that was somewhat effective in certain cases, and could be used with no anaesthesia, but still lacked predictable efficacy. More recently, intra-lesional injections of agents such as Verapamil and clostridial collagenase have been tried, but with very limited success.
Of the injection methodologies, those involving clostridial collagenase appear to exhibit the most consistent efficacy, though still quite limited in effect and duration. Collagenase is likely effective through its ability to dissolve collagen, the major component of the plaque of Peyronie""s disease.
Both external beam radiation treatment and intra-lesional implantation of radium seeds have been tried since the turn of the 20th century. In 1921, Sonntag reviewed this practice and claimed that these treatments were actively detrimental. Despite this, radiation therapy had been used in many clinics over the years and some authorities still claim that success can be anticipated if a radiation regimen is initiated early in the course of the disease. Radiation treatment is also said to be particularly effective for treating patients whose predominant symptom is pain (as opposed to severe disfigurement).
As technologies have evolved, so have the associated energy sources which have been applied to treat Peyronie""s disease. Early in the 20th century, diathermy current was used to generate heat to treat the plaque and eventually low voltage electrical devices were developed and sold for use in the home. Perhaps the most imaginative variant was the technique known as histamine iontophoresis. This combined the use of electrodes with a xe2x80x9cplaque bustingxe2x80x9d solution that was supposedly absorbed into the penis when an electrical gradient was applied. In more recent times, both ultraviolet light and local ultrasound have surfaced and submerged in the treatment history.
Not surprisingly, the inevitable application of laser technology has recently emerged as a means of xe2x80x9cvaporizingxe2x80x9d the plaque. Again, the efficacy of this latest treatment is open to serious question.
The staggering array of treatment options for Peyronie""s disease (failed attempts, really), and the invested effort, cost and intellectual energy which they represent, are testament to the serious need that remains for an effective treatment for Peyronie""s disease, and one which patients can tolerate from cost, comfort and convenience perspectives.
All-in-all, there is simply no truly effective treatment of Peyronie""s diseasexe2x80x94a disease which often produces such severe discomfort and distress that sufferers have been willing to endure such treatments as penile injections.
C. Other Fibrotic Disorders
As mentioned above, Peyronie""s disease is not the only condition which manifests itself via sub-dermal plaques. Dupuytren""s contracture of the hand, and Ledderhose Fibrosis are additional examples. Discussions herein concerning the treatment regimen and efficacy in the treatment of Peyronie""s disease through practice of the present invention are equally applicable to such other fibrotic disorders.
The medicaments of the present invention have been used in treating both Dupuytren""s contracture of the hand, and Ledderhose Fibrosis. In these instances, efficacy in treating Dupuytren""s contracture of the hand, and Ledderhose Fibrosis through topical application of the present medicaments equal that of treating Peyronie""s disease.
D. Erectile Dysfunction
Fibrosis is a common response to numerous conditions, including but not limited to the following:
Aging
Tissue necrosis
Trauma or Injury
Connective Tissue Disease
Hypertension
Diabetes
Arterial Insufficiency
Atherosclerosis
Fibrosis of cavemosal smooth muscle tissue results in the loss of elasticity of this smooth muscle tissue, thereby interfering with the normal expansion of the cavernosal chambers when filled with arterial blood. Therefore, a partial penile erection or no erection may occur.
Erectile dysfunction due to fibrosis is common from the fifth through the eighth decade of life, while the capacity for erection often is not changed. A hypothesis of the present inventor was that, because fibrosis underlies certain forms of erectile dysfunction, his topical, calcium channel blocker medicaments might be efficacious in treating such forms of erectile dysfunction as arise from fibrosis because of the common causative roots of fibrosis-related erectile dysfunction and Peyronie""s diseasexe2x80x94excessive formation of connective tissue.
As discussed below, the inventor""s hypothesis proved correct.
E. Reduction of Existing Scars
Yet another use for compositions and methods of use of the present invention involves the remediation of existing scars. Preliminary research indicates that topical calcium channel blocker preparations of the present invention exhibit a high degree of efficacy in reducing objective manifestations of scar tissues. Compositions of the present invention have been applied in a like dosage and periodicity as described above to a variety of scar types with thus far successful results. In the limited number of cases to date, the dimensions and, when applicable, aberrant coloration of existing scars were substantially reduced and similar time frames as those observed in the use of such compositions in the treatment of the sub-dermal plaque accumulations of Peyronie""s disease-like maladies. Indications, particularly from plastic surgeons, are to the effect that the treatment of existing scarring through use of the present compositions appears to provide scar remediation with an unprecedented combination of ease of treatment, lack of pain and efficacy.
It is an object of the present invention to provide a novel medicament useful in the treatment of connective tissue disorders, exemplified by sub-dermal plaque formation and accumulation, such as Peyronie""s disease, Dupuytren""s contracture, Ledderhose Fibrosis and fibrosis of muscle tissue such as underlies erectile dysfunction.
It is another object of the present invention to provide a novel and unobvious medicament useful in the treatment of conditions characterized by hyperprolipheration of connective tissue such as Peyronie""s disease, Dupuytren""s contracture, Ledderhose Fibrosis, and scarring.
It is another object of the present invention to provide a novel and unobvious medicament useful in the treatment of fibrotic tissue disorders, which medicament is more effective than existing means for treatment.
It is another object of the present invention to provide a novel and unobvious medicament useful in the treatment of connective tissue disorders through the non-invasive, topical application thereof.
It is another object of the present invention to provide a novel and unobvious medicament useful in the treatment of connective tissue disorders through the non-invasive, topical application thereof, which topical application is of at least equal efficacy than invasive and/or less convenient treatment regimens.
In satisfaction of these and related objectives, Applicant""s present invention provides a topical medicament and associated methodology for use thereof, through the use of which Peyronie""s disease, Dupuytren""s contracture, Ledderhose Fibrosis, and related fibrotic tissues disorders (including scarring and fibrosis-based erectile dysfunction) may be effectively, cost effectively, and painlessly treated.
The invention, although exemplified by specific embodiments which are based upon, or rely on the use of specific calcium channel blockers, is not limited to such species. Rather, observations by the present inventor indicate that when coupled with a suitable carrier for transdennal delivery, all thus-far-evaluated calcium channel blockers effect reduction of fibrotic tissue disorder symptoms. Therefore, the true scope of the invention encompasses preparations and methods of use facilitating or involving the use of transdermal application of calcium channel blockers in the treatment of fibrotic tissue disorders which exhibit subdennal plaque accumulations (Peyronie""s disease, Dupuytren""s contracture, and Ledderhose Fibrosis, for example) or scarring.
The medicament of the present invention is a topical gel which has repeatably effected, in many cases, a complete reversal of perceptible Peyronie""s disease symptoms, and in all cases, a substantial reduction of such symptoms to a substantially greater degree and substantially higher incidence than previously experienced by patient populations over-all, and in individual instances wherein patients had previously attempted alternative treatment regimens.
All observations of efficacy of the present compositions and methods arise from physician-supervised and prescribed treatment regimens involving use of the medicaments of the present invention. In most cases to date, use of the present medicaments and prescribed treatment regimens followed prior, wholly or substantially unsuccessful attempts to treat patients"" fibrotic tissue disorders, most such cases to date involving Peyronie""s disease. Recent studies (as discussed below) involve the treatment of erectile dysfunction though use of the medicaments taught herein. These later studies indicate that use of topical calcium channel blocker medicaments taught herein are highly effective in treating erectile dysfunction which appear to relate to fibrosis of cavernosal smooth muscle tissue.
In a experimental study, 142 patients reporting decreased quality erections were treated with topical Verapamil (80 mg/mL). One hundred thirty four (94.3%) experienced improvement of erectile rigidity and/or improvement of penile girth upon erection. These patients applied 0.5 mL of the Verapamil topical compound to the entire shaft of the penis twice a day. The length of treatment varied from one to several months, with the mean treatment period being 3.5 months. Patients were either examined or interviewed and counseled at least every thirty days in order to evaluate progress and monitor side effects. The only side effect reported was contact dermatitis in less than one percent of the patient population. This side effect was easily controlled with topical corticosteroids.
Similar results have been observed in patients treated with a topical Nifedipine compound (40-60 mg/ml) or a combination of Verapamil and Nifedipine.
Formulations for the topical Verapamil, Nifedipine, and combination Verapamil-Nifedipine are identical to those provided herein with respect to Peyronie""s Disease and the other discussed connective tissue disorders.
Upon initial suggestion of the present compositions and methods for use in treating fibrotic or connective tissue disorders, the present inventor experienced, at the hands of experienced practitioners in the field, expressions of serious doubt as to efficacy, and, in some cases, outright ridicule. The stated basis for such initial doubts and criticisms related to the fact that intralessional injections of precisely the same substances (calcium channel blockers) in the attempted treatment of Peyronie""s disease and similar fibrotic tissue disorders had yielded very sporadic and limited results. The present inventor was told repeatedly by those experienced in the treatment of fibrotic tissue disorders (Peyronie""s disease, in particular) that a topical preparation based on calcium channel blockers could xe2x80x9cneverxe2x80x9d have efficacy in view of the failure of injections of the same substances directly into the plaques of these conditions. As mentioned previously, actual experience teaches that the strikingly counter-intuitive effect of the compositions and methods of the present invention in the treatment of fibrotic tissue disorders is very much realxe2x80x94a fact born out by the substantial commercial success of the present medicaments in a very short time (less than a year at the time of preparation of this application) and with no commercial marketing whatsoever, as well as the immediate replacement of existing treatment regimens by the medicaments and methods of the present invention by numerous medical practitioners.
Another remarkable use of the medicaments of the present invention (all based on topically applied calcium channel blocker preparations) relates to the treatment of existing scars, such as arise from injury and surgical procedures. Preliminary studies indicate that the topical channel blocker preparations of the present invention, when applied to existing scars (as opposed to sites of injury in any attempt to prevent scar formation ab initio) substantially reduces the dimensions and color aberrations of scars.